GHRP-2, GHRP-6, Hexarelin — the older GH-releasing peptides and why newer ones replaced them

He spends the next two decades trying to figure out what that switch is.

The growth hormone story up to that point had been fairly linear. Growth hormone itself was identified in the 1920s. GHRH — the hypothalamic signal that prompts the pituitary to secrete GH — was characterized structurally in 1982, another Tulane contribution. The framework was: hypothalamus releases GHRH, pituitary responds, GH goes into circulation, somatostatin provides the counterbalancing brake. A clean two-signal model, well understood. What Bowers was watching couldn't fit into that model, because his peptides weren't GHRH analogs. They weren't touching the known receptor. They were producing GH pulses through something else.

What he was looking at, though he wouldn't know this in full until much later, was the ghrelin receptor. Or more precisely, the receptor that ghrelin would eventually be found to activate — the growth hormone secretagogue receptor type 1a, GHS-R1a. Ghrelin itself wasn't identified until 1999, by a Japanese team led by Masayasu Kojima. The receptor had been pharmacologically characterized by that point — Bowers and colleagues had been probing it for twenty years with synthetic ligands — but the endogenous peptide that belonged to it had remained unknown. This is unusual in biology: the key was found and used to open doors before anyone knew there was a lock, let alone that a natural key existed.

The peptides Bowers developed across the 1980s and 1990s trace a clear arc. GHRP-6 came first — a six-amino-acid peptide, hence the name, synthesized in the early 1980s and representing the first proof of concept that a small, fully synthetic peptide could robustly stimulate GH release via this newly mapped pathway. It worked. It produced meaningful GH pulses. It also produced pronounced appetite stimulation, because the receptor it was activating — what would later be named the ghrelin receptor — is deeply involved in hunger signaling. That appetite effect was interesting from a basic science perspective and potentially useful in certain clinical applications, but it flagged early that this receptor wasn't cleanly dedicated to GH.

GHRP-2 followed, a modified version with a slightly different amino acid sequence and a somewhat cleaner pharmacological profile. Where GHRP-6 was the demonstration that the concept worked, GHRP-2 was the refinement — stronger GH stimulation relative to GHRP-6, somewhat less pronounced appetite stimulation, though still present, and a broader research interest that eventually attracted pharmaceutical investment. European and Italian researchers pursued GHRP-2 in clinical contexts for short stature and GH deficiency. Pfizer and Wyeth examined it at various stages. The compound showed efficacy in stimulating GH. The problem wasn't efficacy. The problem was pharmacological messiness — the cortisol and prolactin elevations that came along with the GH response, and the appetite effects that complicated use in certain populations.

Hexarelin appeared in the early 1990s, developed largely in Italy and positioned as the most potent entry in the series. Its amino acid sequence differed from GHRP-6 at two positions, and those differences produced a more powerful GH release than either predecessor. Italian researchers were particularly interested in its cardiovascular effects — an unusual property that later research would suggest operated through a receptor distinct from GHS-R1a, possibly the CD36 scavenger receptor. Hexarelin appeared to have direct cardiac signaling independent of GH, which opened a research thread that the cardiology community followed for some years. But Hexarelin had a serious practical limitation: of the three older GHRPs, it produced the most pronounced receptor desensitization. The GHS-R1a receptor downregulated quickly under sustained Hexarelin exposure, and the GH response flattened out. You had the most potent compound in the series combined with the fastest burnout.

Throughout the late 1990s, there was genuine pharmaceutical interest in this class. The ghrelin receptor had been mapped. The compounds worked. The question was whether they could be optimized into a drug — particularly an oral drug, since injectables carry a large clinical and commercial burden. Merck pursued a different strategy: MK-677, a non-peptide, orally bioavailable GHS-R1a agonist, emerged from their research as a synthetic mimic of these peptide effects that survived the digestive tract. MK-677 never reached FDA approval either, but it represented a pharmacological direction — small-molecule, oral, sustained-action — that the injectable peptide series couldn't match.

The other direction was selectivity. GHRP-2, GHRP-6, and Hexarelin all produced GH through the ghrelin receptor, but they also produced cortisol, prolactin, and appetite stimulation through the same receptor or associated pathways. The field began to ask whether you could separate the GH effect from the side-effect profile. Ipamorelin, developed later in the 1990s and characterized extensively in the early 2000s, was the answer to that question. It's a five-amino-acid peptide — more compact than the older GHRPs — that activates GHS-R1a with considerably more selectivity. It produces robust GH stimulation with minimal cortisol elevation, minimal prolactin elevation, and far less appetite stimulation than GHRP-6 or GHRP-2. In preclinical and early clinical studies, it simply had a cleaner profile.

The displacement of the older GHRPs by Ipamorelin in research and compounding contexts is a story about selectivity winning over raw potency. GHRP-6's appetite effects made it practically limited for anyone not trying to gain weight. GHRP-2's cortisol elevation raised questions for anyone using the compound long-term. Hexarelin's desensitization made it impractical for sustained use. Ipamorelin did less collateral activation and desensitized more slowly. For most of the applications people cared about — supporting GH physiology in aging adults, recovery, sleep quality — a selective, manageable compound was more useful than a potent, messy one.

None of these compounds — GHRP-2, GHRP-6, Hexarelin, Ipamorelin — reached FDA approval. GHRP-2 and Hexarelin went through enough development stages to accumulate meaningful clinical data, but pharmaceutical investment eventually moved on. The reasons are partly about side-effect profile, partly about the business logic of drug development in the GH space (where exogenous HGH already existed as a therapy), and partly about the difficulty of getting an injectable peptide through the full FDA approval process when the commercial case is uncertain. Compounded versions of these peptides exist outside the pharmaceutical mainstream, prepared by licensed compounding pharmacies and accessed through prescribing providers who work in this space.

What the older GHRPs accomplished, regardless of their commercial fate, was foundational. Cyril Bowers's strange observation in the 1970s — that enkephalin analogs were raising GH — became, over twenty years of careful peptide chemistry, the discovery of an entirely new axis of GH regulation. The field learned that the pituitary could be signaled through two distinct pathways: GHRH (the classical signal from the hypothalamus) and the ghrelin receptor (a separate mechanism, later shown to involve a gut-derived hormone that the brain was listening to). GHRP-6, GHRP-2, and Hexarelin were the tools that traced that second pathway into view. Without them, the ghrelin receptor might have been characterized years later, and Ipamorelin and MK-677 — the cleaner second-generation tools — would have had no foundation to build on.

The history of GH-releasing peptides is, in this sense, a story about how science actually moves: not through linear refinement of a known mechanism, but through anomalous observations that survive long enough to become discoveries. A peptide that behaved strangely in a Tulane lab became the conceptual origin of a receptor, a hormone, and an entire field of secretagogue pharmacology. The compounds that opened that territory — imperfect, side-effect-laden, never quite approved — remain in circulation not because they're optimal, but because they're original. They did the thing first. Everything that followed them, including everything that replaced them, starts with what they found.